Guy McKhann, M.D.

Johns Hopkins University

Funded in April, 2016: $100000 for 1 years

For the first time, researchers may be
able to define the interrelated functional and structural brain changes that
evolve over time in cognitively healthy adults who eventually develop
Alzheimer’s disease (AD). Identifying the earliest brain signs of AD would
enable clinical testing of experimental interventions to prevent or arrest degeneration
of brain cells and their synapses (connections) that leads to AD before this
damage becomes irreversible.

More than a decade before adults with
memory problems are diagnosed with “mild cognitive impairment” (MCI), which
often progresses to AD, the brain is building up abnormal “amyloid” and “tau”
proteins. Symptoms only emerge when enough amyloid has accumulated between
brain cells to begin damaging synapses so that cells cannot communicate, and
when enough tau has accumulated within brain cells to lead to the cells’ death.
By then, it is already too late to reverse or treat this interactive neurodegeneration.
Since a significant proportion of those with MCI will eventually develop AD, it
is essential to intervene prior to MCI onset by determining when and where
amyloid and tau changes first occur and how their actions interrelate.

The investigators began investigating
these questions in a population of cognitively healthy adults who have been
followed now for two decades. The study was based on evidence indicating that
certain measures in cerebral spinal fluid (CSF) reflect brain amyloid and tau
accumulation even prior to the onset of MCI. They have been correlating changes
in participants’ CSF with changes in the brain as assessed by MRI and changes
in participants’ cognitive functioning.

Newly added to this study are two more
recently developed imaging techniques to provide more direct measures of
amyloid and tau accumulation and their effects in the brain. One is PET-PiB
imaging that directly measure amyloid levels. While methods to directly image
tau are being developed, investigators are using “resting state fMRI” (rs-fMRI)
in participants who are not undertaking a specific task to measure changes in functional
network connections.

With the groundbreaking development of a
multi-modal brain atlas that has taken years to develop, the researchers now
will be able to examine not only PET and MRI imaging changes individually but
also their inter-related measures of changes in the same brain areas. They will
correlate these measures with changes that occurred in participants’ CSF
samples over time, to address a range of questions concerning the
pre-symptomatic phase of AD.

Among these are: 1) Do the same brain
areas that show high amyloid accumulation also show reduced volume (cell
death), reduced neural connections, and reduced activity in functionally
connected networks when no task is being performed? 2) Are certain brain regions that show reductions
in volume (cell death), connections and functionally connected networks more
strongly correlated with increased CSF levels of tau, while other regions are
more strongly correlated with increased CSF levels of amyloid? 3) Is the combined measure of cell death and
reduced neural connectivity associated with CSF measures of tau? If so, can
this combined measure serve as a proxy for the amount of tau accumulation in
the brain?

Researchers expect that the analyses
addressing these and related questions will provide additional insights into the
interrelated damage to specific brain areas related to varying levels of tau
and amyloid accumulation that are seen before any memory problems occur. They
anticipate that this information can be predictive of which healthy adults are
likely to develop clinical symptoms of MCI and AD in the coming years. With
this predictive capacity, clinical researchers could test experimental
therapies in pre-symptomatic adults at the earliest stage when treatments have
the greatest likelihood of arresting disease progression. Moreover, grouping
pre-symptomatic clinical trials participants according to degree of preclinical
disease would strengthen outcome assessments of experimental therapies.

Significance:
The study may for the first time provide the integrated information necessary
to characterize pre-clinical AD and facilitate clinical trials in at-risk
cognitively healthy adults early enough for the interventions to arrest
progression to AD.

Guy McKhann, M.D.

Guy M. McKhann, M.D. is
Professor of Neurology at the Johns Hopkins University (JHU) School of Medicine,
with a joint appointment in the School’s Department of Neuroscience. He was the
founding chairman of the School’s Neurology Department and also was the
founding director of the University’s Zanvyl Krieger Mind/Brain Institute. Dr. McKhann has authored more than 200
publications. His clinical research has included
studies of the Guillain-Barre Syndrome, which included research programs in the
United States as well as in China. His most recent research has focused on the
role of vascular factors in cognitive decline. He was co-editor for many years of the neurology textbook, Diseases
of the Nervous System: Clinical Neurobiology. He and his colleague
(and wife) Dr. Marilyn Albert published a book about aging and the brain for
the general public entitled Keep Your Brain Young. Dr.
McKhann has been involved with a number of scientific organizations, including
as president of the American Neurological Association. Dr. McKhann attended Harvard University and received his MD degree
from the Yale University School of Medicine.

KEYWORDS

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